UCSD researchers hope protein discovery could lead to diabetes treatments

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Editor's note: In observance of Diabetes Awareness Month, The Daily Transcript will feature weekly stories highlighting the efforts under way in San Diego to help in the fight against diabetes. The following article is another in the series:

A team of local researchers, working with colleagues in Switzerland, made a discovery about insulin in mice that they think could lead to new diabetes treatments in humans.

Scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland discovered that by knocking out a key regulatory protein, they could make mice predisposed to diabetes become more sensitive to insulin. A hallmark of diabetes is resistance to insulin.

The research was published in the Nov. 11 issue of the journal Cell.

The research focused on a protein called nuclear receptor co-repressor (NCoR), which is found in many cells and stimulates genes, turning them on an off. NCoR was known to have a major effect on a different protein -- Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma), which regulates fatty acid storage and glucose metabolism -- but was also known to act on other receptors as well.

Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego and senior author of the paper, created mice whose fat cells lacked NCoR. Though bred to be obese and prone to diabetes, the team discovered that these mice displayed enhanced insulin sensitivity in liver, muscle and fat, and decreased systemic inflammation -- all the opposite of what a diabetes patient would experience.

“When NCoR was deleted, insulin sensitivity in the whole animal increased dramatically compared to normal obese mice, which remained insulin resistant. The sensitivity occurred not just in adipocytes (fat cells), but in all cells,” said Olefsky. “With NCoR knocked out of adipocytes, PPAR-gamma becomes active. This produces a robust increase in systemic insulin sensitivity.”

Olefsky said this could open up new possibilities for diabetes treatments in humans. NCoR’s role as a major co-repressor has been known, but it was considered a poor drug target because inhibiting it could cause unwanted de-repression in some cell types, producing adverse side effects. Olefsky said the newly discovered specificity of NCoR revitalizes the idea that NCoR may be an excellent drug target for type 2 diabetes and other insulin resistant diseases.

“If researchers can make a drug that’s tissue-specific, repressing NCoR could be a powerful way to boost insulin sensitivity. It’s doable," he said." Already, we can create drugs that specifically target fat and liver cells. That might be good enough to produce a system-wide benefit.”

Funding for this study came, in part, from the National Institutes of Health, the EU Ideas Program, the Swiss National Science Foundation and the Eunice Kennedy Shriver National Institute of Child Health & Human Development as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.